The overall long-term objective of this project is to develop methods and tools for optimizing radiation therapy of cancers. Better outcome of radiation therapy can be achieved by delivering highly optimized and individualized treatments. The Intensity Modulated Radiation Therapy, functional imaging, image-guided therapy, 4D-CT and 4D Monte Carlo dose calculation provide means to implement high precision individualized treatment strategies. These developments have a potential to improve outcomes of radiotherapy to make the most of them, we need tools to evaluate their clinical merit and to quantify the clinical consequences of any proposed radiation therapy plan. This problem is complex and difficult, as it requires the knowledge of dose-volume response characteristics of tumors and normal organs and tissues, and biophysical models to summarize, quantify, and extrapolate this knowledge to new situations. It is typically assumed that the important sub-units of normal organs or tumors are affected by radiation independently of what happens to other surrounding sub-units. However, there are anatomical, biological, and physiological indications, as well as clinical and experimental data suggesting that this is unlikely to be the case. Therefore, the major thrust of this proposed work is to investigate the importance of, and consequences of, co-operative phenomena in response of normal tissues and tumors to radiation. The specific aims of the research proposal are fourfold: a) identify problems with the existing praxis of modeling and predicting tissue response to radiation; b) investigate percolation theory to model dose-volume effects in radiation therapy; c) analyze clinical and experimental data to determine the parameters for percolation theory-based models of tissue response to radiation; d) initiate comparative studies of various state-of-the-art radiation therapy techniques using the developed models of tissue response to radiation. Considering the intrinsic complexities of the underlying biology and the whole process of radiation treatment delivery, Monte Carlo techniques will be extensively used to simulate various important biological and dosimetric effects and to quantify their relevance for optimizing radiation treatment. It is expected that the results of the proposed research will improve the efficacy of radiation therapy by providing tools for optimizing and individualizing radiation treatment, and for quantitative evaluating new technical developments aiming at improving the precision of radiation treatment.